Orally disintegrating dosage form for administration of avanafil, and associated methods of manufacture and use

ABSTRACT

Formulations are provided for the oral administration of avanafil, a Type V phosphodiesterase inhibitor (“PDE V inhibitor”), and analogs thereof. The formulations are orally disintegrating tablets (ODTs) that rapidly dissolve or disintegrate in the oral cavity. The tablets contain an absorption enhancing composition that increases the duodenal absorption of the active agent, following transfer from the low pH environment of the stomach to the more basic pH of the duodenum. Methods for administering the active agent using the dosage forms are provided. The invention also encompasses a method of selecting components and compositions to incorporate in the formulations which will facilitate increased absorption of the active agent in the duodenum and thus serve as “absorption enhancing compositions” herein. Also provided are methods for manufacturing orally disintegrating tablets to optimize the physical properties of the dosage forms, particularly hardness and disintegration time.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/014,093 filed Jun. 21, 2018, which is a continuation of U.S. patentapplication Ser. No. 14/714,028 filed May 15, 2015 (now U.S. Pat. No.10,028,916), which claims priority to, and the benefit of, U.S.Provisional Patent Application Ser. No. 61/994,349 filed May 16, 2014,the entire contents of each of which are herein incorporated byreference in their entireties.

FIELD OF INVENTION

This invention relates generally to the field of drug delivery, and moreparticularly relates to an orally disintegrating dosage form for theadministration and rapid absorption of a Type V phosphodiesteraseinhibitor such as the N-heterocyclic-substituted ketone avanafil. Theinvention additionally relates to a method for manufacturing orallydisintegrating dosage forms, and to a method for selecting compounds andcompositions that enhance the absorption of basic active agents. Theinvention has utility in the fields of medicine and pharmaceuticalformulation.

BACKGROUND OF THE INVENTION

In general, it is known that cyclic guanosine monophosphate (“cGMP”),which is an intracellular secondary messenger, is decomposed andinactivated by cyclic nucleotide phosphodiesterases (“PDEs”) thathydrolyze cGMP into 5′-GMP. Such phosphodiesterases are widelydistributed in many cell types and tissues of the living body. When PDEactivity is inactivated by a an inhibitor of a cGMP-degradingphosphodiesterase, the level of cGMP in cells is increased, in turntriggering several physiological responses, including relaxation ofvascular smooth muscle, relaxation of bronchial smooth muscle, andinhibition of platelet aggregation.

Moreover, it has been reported that certain cGMP-specific PDE inhibitors(i.e., inhibitors of phosphodiesterase Type V, or “PDE V inhibitors”)are useful in the treatment of diseases caused by a functional disorderof cGMP signaling, including hypertension, angina pectoris, myocardialinfarction, chronic or acute heart failure, pulmonary hypertension, etc.(see, e.g., International Patent Publication No. WO 96/05176), andprostatic hyperplasia (see Australian Patent Publication No. 9955977).It has also been reported that PDE V inhibitors can be useful in thetreatment of female sexual dysfunction (see, e.g., U.S. Pat. No.6,469,016 to Place et al., of common assignment herewith to Vivus, Inc.;and Vemulapalli et al. (2000) Life Sciences 67: 23-29), diabeticgastroparesis (Watkins et al. (2000) J. Clin. Invest. 106: 373-384),achalasia (Bortolotti et al. (2000) Gastroenterology 118: 253-257),diarrhea (Mule et al. (1999) Br. J. Pharmacol. 127: 514-520),constipation (Bakre et al. (2000) J. Cell. Biochem. 77: 159-167) andasthma (Turner et al. (1994) Br. J. Pharmacol. 111: 1198-1204).

Furthermore, sildenafil,1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-phenylsulfonyl]-4-methylpiperazinecitrate, a cGMP-specific PDE V inhibitor, is now widely prescribed forthe treatment of penile erectile dysfunction (as Viagra®, Pfizer), asare the cGMP-specific PDE V inhibitors tadalafil (as Cialis®, LillyICOS), and vardenafil (as Levitra®, Bayer AG). However, these PDE Vinhibitors have been reported to have side effects such as headache,facial suffusion, gut disorder, rhinitis, color sense disorder, penileerectile continuance, back pain, abdominal pain, and nausea (see, e.g.,Irwin et al. (1998) The New England Journal of Medicine338(20):1397-1404; Morales et al. (1998) International Journal ofImpotence Research 10(2): 69-73; and Goldenberg (1998) ClinicalTherapeutics 20(6): 1033-1048). It has also been reported that the sideeffects of sildenafil affect vision, including blurriness and loss ofperipheral vision.

In U.S. Pat. No. 6,656,935 to Yamada et al. (Tanabe Seiyaku Co. Ltd.,Osaka, JP), the synthesis of a new class of cGMP-specific PDE inhibitorsis described. These compounds are N-heterocyclic-substituted compoundshaving the general structure (I)

wherein: Ring A is a substituted or unsubstituted nitrogen-containingheterocyclic group; R¹ is a substituted or unsubstituted lower alkylgroup, a substituent having the formula —NH-Q-R³ wherein Q is a loweralkylene group or a single bond and R³ is a substituted or unsubstitutednitrogen-containing heterocyclic group, or a substituent having theformula —NH—R⁴ wherein R⁴ is substituted or unsubstituted cycloalkyl; R²is substituted or unsubstituted aryl; and one of Y and Z is ═CH— and theother is ═N—, and also include pharmaceutically acceptable salts of thecompounds. These compounds, particularly4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide,or “avanafil,” having the structure

are particularly useful in the prophylaxis or treatment of erectiledysfunction with few side effects.

Administration of these therapeutic agents for the treatment of erectiledysfunction is generally on an as-needed basis rather than as part of anongoing dosage regimen. It is also desirable that any erectiledysfunction pharmacotherapy be fast acting, so that a minimum ofscheduling or advance planning is required prior to sexual activity.Although “immediate release” or “rapid release” dosage forms, includingorally disintegrating tablets, have been known in the art for some time,various factors can significantly reduce the absorption of drugs fromsuch tablets. For instance, certain drugs such as avanafil and itsanalogs are soluble in aqueous media at a low pH, but at elevated pH,such as that of the duodenum, the drug can precipitate quickly uponleaving the stomach and entering the duodenum, significantly reducingthe likelihood of rapid absorption. If one could maintain a low enoughlocal pH for the drug to remain in a dissolved state, absorption wouldnot be a problem; there is difficulty, however, in maintaining a locallow pH in the duodenum.

SUMMARY OF THE INVENTION

The present invention is directed to the aforementioned need in the artand provides an oral dosage form that provides for rapid absorption ofavanafil or an analog thereof. Rather than attempting to maintain alocally lower pH as the drug enters the duodenum, i.e., in order topreclude quick precipitation and aggregation as discussed above, theinvention involves formulating the dosage form to include means forreducing precipitation and aggregation as the drug is released from thestomach and enters the duodenum. The invention makes use of increasedsurface area, which, in part, increases absorption rate, and alsoincorporates into the dosage form at least one component that reducesprecipitation and aggregation of the drug in the duodenum. By “reducingprecipitation and aggregation” is meant: delaying the onset ofprecipitation; delaying the onset of aggregation; reducing the rate atwhich precipitation occurs; and/or reducing the rate at whichaggregation occurs. An objective measure by which reduction ofprecipitation and aggregation may be evaluated is described in Example2, in which various avanafil formulations are initially dissolved inwater at a pH of 2.5, the pH of the solution is raised to 7.0, and lighttransmission as a function of time is recorded. Reduction ofprecipitation and aggregation may be defined accordingly as occurringwhen a composition displays less than a 60% reduction in transmission atafter ten minutes at the elevated pH; this is equivalent to anasymptotic transmission of 60% at ten minutes following the upwardadjustment of pH.

In a first embodiment, then, the invention provides an orallyadministrable formulation comprising a therapeutically effective amountof avanafil, a means for reducing precipitation and aggregation of theformulation as drug is released from the stomach and enters theduodenum, and a pharmaceutically acceptable carrier, wherein the meansfor reducing precipitation and aggregation comprises an absorptionenhancing composition.

In another embodiment, the invention provides a method for administeringa PDE V inhibitor to a subject by orally administering to the subject aformulation or dosage form as provided herein. Administration isgenerally not carried out within the context of an ongoing, regular(e.g., daily) dosage regimen, but rather may be and preferably isconducted on an as-needed basis, since the preferred formulations hereinare orally disintegrating dosage forms that provide for rapid releaseand a short time to achieve an effective blood level of the activeagent. When indicated for erectile dysfunction, then, administration ofsuch dosage forms can be immediately prior to sexual activity, generallyabout fifteen minutes to about three hours prior to sexual activity, anadvantage of the invention that eliminates the awkwardness andinconvenience of scheduling or otherwise planning sexual activity.Avanafil, a PDE V inhibitor, is also administered using the method ofthe invention to prevent or treat other disorders, adverse conditions,and diseases that are responsive to administration of a PDE V inhibitor,including, but not limited to, hypertension, angina pectoris, myocardialinfarction, heart failure, pulmonary hypertension, prostatichyperplasia, female sexual dysfunction, neurogenesis, neuropathy,Alzheimer's disease, psoriasis, skin necrosis, metastasis, baldness,nutcracker esophagus, anal fissure, hemorrhoids, insulin resistancesyndrome, hypoxic vasoconstriction, and blood pressure stabilization.

The invention also provides a method for manufacturing an orallydisintegrating dosage form having the desired characteristics discussedherein. In one embodiment, the method comprises a wet granulationtechnique involving an initial step in which a fraction, i.e., some butnot all, of the formulation used to prepare the dosage form, is mixed,granulated and dried, a second step in which the remainder of theformulation is blended in, and, finally, compaction to prepare therapidly disintegrating oral dosage form. Generally, the first fractionof the formulation contains active agent, water or an alternativesolvent, preferably an aqueous solvent, a porous binder, and adisintegrant, preferably but not necessarily a superdisintegrant, suchthat the initial step of the process provides active agent granules,while the remainder of the formulation that is later blended in containsa lubricant, additional disintegrant, and additional porous binder. Whenan absorption enhancing composition is used, it is normally incorporatedin the initial step along with the active agent. In a variation of thismethod, a dry granulation technique may be employed in which the stepsare somewhat analogous but the first step of the process involves rollercompaction or slugging of the combined components followed bygranulation, and the mixture does not contain a liquid.

In a further embodiment, the invention provides a way to evaluate andselect component(s) that may advantageously serve as the absorptionenhancing composition herein, i.e., the composition that improves theabsorption of the active agent by reducing precipitation and/oraggregation of the agent as the agent transitions from the stomach tothe higher pH environment of the duodenum. The method involvesmeasurements of light transmitted at regular time intervals after the pHof an aqueous solution containing the active agent and the candidateabsorption enhancing composition is increased from 2.5 to 7.0, andcomparing the results obtained with that of a control experiment inwhich no candidate absorption enhancing composition is present. Increasein transmission, as a general rule, is indicative of a reduction inprecipitation and/or aggregation induced by the presence of thecandidate absorption enhancing composition. Accordingly, the methodcomprises:

(a) dissolving the active agent in an acidic solution, graduallyincreasing the pH of the solution until a pH of about 7.0 is reached,and then monitoring the extent of precipitation of the active agent overtime as the solution becomes a suspension, by measuring the fraction oflight transmitted through the suspension at regular time intervalsfollowing the increase in pH; (b) dissolving the active agent and acandidate composition in an acidic solution, gradually increasing the pHof the solution until a pH of about 7.0 is reached, and then monitoringthe extent of precipitation of the active agent over time as thesolution becomes a suspension, by measuring the fraction of lighttransmitted through the suspension at regular time intervals followingthe increase in pH; and (c) evaluating the capability of a candidatecomposition to enhance the absorption of a basic active agent in theduodenum by comparing the fraction of light transmitted in (b) to thefraction of light transmitted in (a) at each time interval.

Those candidate compositions that are found to increase the fraction oflight transmitted at one or more time intervals are selected asabsorption enhancers, with preferred absorption enhancers capable ofincreasing the fraction of light transmitted over a prolonged timeperiod, e.g., at least 5-15 minutes. It will be appreciated that themethod is useful in conjunction with screening candidate compositionsthat will enhance the duodenal absorption of basic active agents ingeneral, and is not limited to avanafil per se.

The disclosure provides an orally disintegrating tablet, comprising thefollowing: a therapeutically effective amount of avanafil; an absorptionenhancing composition comprising a surfactant; an orally disintegratingcomposition comprising a disintegrant; and a porous component in apharmaceutically acceptable carrier. In certain embodiments of thetablets of the disclosure, the tablet does not comprise fumaric acid,tartaric acid, succinic acid, malic acid, ascorbic acid or asparticacid.

Tablets of the disclosure may be designed to disintegrate within an oralcavity within in less than a minute while exhibiting a minimal hardness.In certain embodiments of the tablets of the disclosure, the tabletdisintegrates within an oral cavity within about 45 seconds and exhibitsa hardness of greater than about 30 N. In certain embodiments of thetablets of the disclosure, the tablet disintegrates within an oralcavity within about 30 seconds and exhibits a hardness of greater thanabout 15 N. In certain embodiments of the tablets of the disclosure, thetablet disintegrates within an oral cavity within about 15 seconds andexhibits a hardness of greater than about 7.5 N. Disintegrants of thetablets of the disclosure may be superdisintegrants.

Porous components of the tablets of the disclosure may, for example,comprise porous mannitol.

Surfactants of the tablets of the disclosure may comprise a polymericcomponent that mitigates the precipitation of avanafil in an aqueousmedium as pH increases from about 2.5 to about 7.0. In certainembodiments, the polymeric component of a tablet of the disclosure isnonionic and mitigates the precipitation of avanafil in an aqueousmedium as pH increases from about 2.5 to about 7.0 by delayingprecipitation, reducing the rate of precipitation, decreasing the extentof precipitation, or any combination of the foregoing. Polymericcomponents of the tablets of the disclosure may comprise a hydrophilicsegment and a hydrophobic segment. Polymeric components of the tabletsof the disclosure may comprise a polyoxyethylene-polyoxypropylenecopolymer. Polymeric components of the tablets of the disclosure maycomprise poloxamer 407.

The proportion of avanafil in a tablet of the disclosure may comprise orconsist of about 10 wt. % to about 50 wt. % of the tablet. Theproportion of avanafil in a tablet of the disclosure may comprise orconsist of 10 wt. % to 50 wt. % of the tablet. In other words, in atablet of the disclosure, the avanafil or proportion of avanafil mayrepresent in the range of about 10 wt. % to about 50 wt. % of thetablet.

The proportion of avanafil in a tablet of the disclosure may comprise orconsist of about 70 wt. % of the tablet. The proportion of avanafil in atablet of the disclosure may comprise or consist of 70 wt. % of thetablet. In other words, in a tablet of the disclosure, the avanafil orproportion of avanafil may represent up to about 70 wt. % of the dosageform.

The disclosure provides a method for administering a PDE V inhibitor toa subject having a PDE V inhibitor-treatable condition selected fromerectile dysfunction, hypertension, angina pectoris, myocardialinfarction, heart failure, pulmonary arterial hypertension, prostatichyperplasia, female sexual dysfunction, neurogenesis, neuropathy,Alzheimer's disease, psoriasis, skin necrosis, metastasis, baldness,nutcracker oesophagus, anal fissure, hemorrhoids, insulin resistancesyndrome, hypoxic vasoconstriction, and blood pressure stabilization,comprising orally administering the tablet according to claim 1 to thesubject on an as-needed basis.

The disclosure provides method for manufacturing a rapidlydisintegrating oral dosage form, comprising: (a) preparing active agentgranules by (i) blending a pharmacologically active agent in particulateform with a first fraction of a disintegrant and a first fraction of aporous binder, to form an initial mixture, and (ii) granulating theinitial mixture for a predetermined time period at a predeterminedtemperature, to provide the active agent granules; (b) blending theactive agent granules with a lubricant, a second fraction of adisintegrant, and a second fraction of a porous binder, to provide afinal formulation mixture; and (c) compacting the final formulationmixture to prepare the rapidly disintegrating oral dosage form. Incertain embodiments of the methods of manufacturing a tablet of thedisclosure, the granulating step is carried out in a solvent and step(a) further comprises drying the granulation prepared in (ii) prior tostep (b).

In certain embodiments of the methods of manufacturing a tablet of thedisclosure, the porous binder is selected from porous mannitol, porouslactose, and porous glucose and wherein the disintegrant comprises atleast one superdisintegrant.

In certain embodiments of the methods of manufacturing a tablet of thedisclosure, the active agent is avanafil and the method furthercomprises incorporating an absorption enhancing composition into thedosage form, wherein a first fraction of the absorption enhancingcomposition is incorporated in (a) and a second fraction of theabsorption enhancing composition is incorporated in (b).

The disclosure provides a tablet made or manufactured by any method ofthe disclosure. For example, the disclosure provides an orallydisintegrating tablet having hardness of 13.5 N or more, which isobtained by a process comprising the following steps: (a) preparingactive agent granules by (i) blending avanafil in particulate form witha first fraction of a disintegrant and a first fraction of a porousbinder, to form an initial mixture, and (ii) granulating the initialmixture for a predetermined time period at a predetermined temperature,to provide the active agent granules, wherein granulating is carried outin a solvent; (b) drying the active agent granules; (c) blending the dryactive agent granules with a lubricant, a second fraction of thedisintegrant, and a second fraction of a porous binder, to provide afinal formulation mixture; and (d) compacting the final formulationmixture to prepare the rapidly disintegrating oral dosage form.

Other aspects, embodiments, advantages, and variations of the inventionwill be apparent to those of ordinary skill in the art based on thedescription herein and the knowledge of those working in the pertinentfields.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph of normalized transmission fraction versus time forthe control experiment described in Example 2.

FIG. 2 is a graph of normalized transmission fraction versus time forthe experiment conducted using sucrose palmitate, as described inExample 2.

FIG. 3 is a graph indicating the turbidity (FTU) measurements made overtime for the control experiment described in Example 2.

FIG. 4 is a graph indicating the turbidity (FTU) measurements made overtime for the experiment conducted using sucrose palmitate, as describedin Example 2.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, the invention is not limited to specificformulation components, dosage regimens, manufacturing processes,absorption enhancer evaluation techniques, or the like, as such mayvary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only and is notintended to be limiting.

As used in the specification and the appended claims, the singular forms“a,” “an,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an active agent” or“a pharmacologically active agent” includes a single active agent aswell as a combination or mixture of two or more different active agents,reference to “an absorption enhancing composition” includes reference toa single such composition or a mixture of such compositions (with eachsuch composition itself including one or more individual components),reference to “a carrier” or “an excipients” includes mixtures of two ormore carriers and two or more excipients as well as a single carrier orexcipient, and the like.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The terms “active agent,” “pharmacologically active agent” and “drug”are used interchangeably herein to refer to a chemical compound thatinduces a desired pharmacological, physiological effect, i.e., in thiscase, treatment of erectile dysfunction. The primary active agentsherein are inhibitors of phosphodiesterase V (“PDE V inhibitors”). Theaforementioned terms also encompass pharmaceutically acceptable,pharmacologically active derivatives of those active agents specificallymentioned herein, including, but not limited to, salts, esters, amides,prodrugs, active metabolites, conjugates, analogs, and the like. Whenthe terms “active agent,” “pharmacologically active agent” and “drug”are used, then, or when a particular active agent is specificallyidentified, it is to be understood that the term includes not only theactive agent per se but also its pharmaceutically acceptable,pharmacologically active salts, esters, amides, prodrugs, metabolites,conjugates, analogs, etc.

By pharmaceutically acceptable,” such as in the recitation of a“pharmaceutically acceptable carrier,” or a “pharmaceutically acceptableacid addition salt,” is meant a material that is not biologically orotherwise undesirable, i.e., the material may be incorporated into apharmaceutical composition administered to a patient without causing anyundesirable biological effects or interacting in a deleterious mannerwith any of the other components of the composition in which it iscontained. “Pharmacologically active” (or simply “active”) as in a“pharmacologically active” derivative or metabolite, refers to aderivative or metabolite having the same type of pharmacologicalactivity as the parent compound and approximately equivalent in degree.When the term “pharmaceutically acceptable” is used to refer to aderivative (e.g., a salt) of an active agent, it is to be understoodthat the compound is pharmacologically active as well, i.e.,therapeutically effective in the treatment of premature ejaculation.“Carriers” or “vehicles” as used herein refer to conventionalpharmaceutically acceptable carrier materials suitable for drugadministration, and include any such materials known in the art that arenontoxic and do not interact with other components of a pharmaceuticalcomposition or drug delivery system in a deleterious manner.

The term “erectile dysfunction” is intended to include any and all typesof erectile dysfunction, including: vasculogenic, neurogenic,endocrinologic and psychogenic impotence (“impotence” is used here inits broadest sense to indicate a periodic or consistent inability toachieve or sustain an erection of sufficient rigidity for sexualintercourse (see U.S. Pat. No. 5,242,391 to Place et al.); Peyronie'ssyndrome; priapism; premature ejaculation; and any other condition,disease or disorder, regardless of cause or origin, which interfereswith at least one of the three phases of human sexual response, i.e.,desire, excitement and orgasm (see Kaplan, Disorders of Sexual Desire(New York, N.Y. Brunner Mazel Book Inc., 1979)).

The terms “treating” and “treatment” as used herein refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, prevention of the occurrence of symptoms and/or theirunderlying cause, and improvement or remediation of damage. The presentmethod of “treating” erectile dysfunction, as the term is used herein,thus encompasses both prevention of the disorder in a predisposedindividual and treatment of the disorder in a clinically symptomaticindividual.

By an “effective” amount or a “therapeutically effective amount” of adrug or pharmacologically active agent is meant a nontoxic butsufficient amount of the drug or agent to provide the desired effect.The amount that is “effective,” however, will vary from subject tosubject, depending on the age and general condition of the individual,the particular active agent or agents, and the like. Thus, it is notalways possible to specify an exact “effective amount.” However, anappropriate “effective” amount in any individual case may be determinedby one of ordinary skill in the art using routine experimentation.

By “as-needed” dosing, also referred to as “pro re nata” dosing, “pm”dosing, and “on-demand” dosing or administration, is meant theadministration of an active agent at a time just prior to the time atwhich drug efficacy is wanted, e.g., just prior to anticipated sexualactivity, and within a time interval sufficient to provide for thedesired therapeutic effect, i.e., enhancement in sexual desire and insexual responsiveness during sexual activity. “As-needed” administrationherein does not involve priming doses or chronic administration,“chronic” meaning administration at regular time intervals on an ongoingbasis. As-needed administration may involve administration immediatelyprior to sexual activity, but will generally be about 0.25 to 3.5 hours,preferably about 0.5 to 3 hours, and most preferably about 1 to 2.5hours prior to anticipated sexual activity. “As-needed” administrationmay or may not involve administration of a sustained release formulationin advance of anticipated sexual activity, with drug release takingplace throughout an extended drug delivery period typically in the rangeof about 4 to 72 hours.

The term “orally disintegrating tablet” (ODT) is used interchangeablywith the term “rapidly disintegrating tablet” (RDT) to refer to a soliddosage form composed of a tablet that is designed to disintegrate ordissolve rapidly in the oral cavity without need for chewing orswallowing with liquids. Preferred orally disintegrating tablets hereinhave the characteristics set forth by the U.S. Food & DrugAdministration in Guidance for Industry: Orally Disintegrating Tablets(Dept. of Health and Human Services, U.S. FDA Center for Drug Evaluationand Research, December 2008). Generally, then, the preferred tablets ofthe invention exhibit in vitro disintegration times of 30 seconds orless when evaluated using the USP Disintegration Test described in USP24-NF 19 or an equivalent alternative test. As explained in theforegoing section of the U.S Pharmacopoeia, the USP Disintegration Testis conducted by placing the dosage form to be tested in a basket rackassembly, immersing the assembly in a specified fluid at a temperaturebetween 35° C. and 39° C. for a given time period, and raising andlowering the basket in the immersion fluid through a distance of about5.5 cm at a frequency of about 30 cycles per minute. The dosage formsare visually inspected at specified times for complete disintegration,defined in Section 701 of USP 24-NF 19 as the state in which any residueof the dosage form remaining in the basket rack of the test apparatus isa “soft mass having no palpably firm core.” As such, it will beappreciated that the present dosage forms are optimal for rapiddisintegration in the mouth without the need to drink additional water.Adsorption may be through the duodenum or through the oral mucosa.

Active Agents:

In one embodiment, then, an oral dosage form is provided for theadministration and rapid absorption of avanafil. Unless otherwiseindicated, reference to avanafil encompasses avanafil per se as well asN-heterocycle-substituted ketones having the structure of Formula (I)

wherein: Ring A is a substituted or unsubstituted nitrogen-containingheterocyclic group; R¹ is a substituted or unsubstituted lower alkylgroup, a substituent having the formula —NH-Q-R³ wherein Q is a loweralkylene group or a single bond and R³ is a substituted or unsubstitutednitrogen-containing heterocyclic group, or a substituent having theformula —NH—R⁴ wherein R⁴ is substituted or unsubstituted cycloalkyl; R²is substituted or unsubstituted aryl; and one of Y and Z is ═CH— and theother is ═N—, and also include pharmaceutically acceptable salts of thecompounds.

Among the aforementioned compounds, the nitrogen-containing heterocyclicgroup of the “substituted or unsubstituted nitrogen-containingheterocyclic group” for Ring A is a 5- to 10-membered monocyclic orbicyclic nitrogen-containing heterocyclic group, more particularly, a 5-or 6-membered nitrogen-containing heteromonocyclic group and an 8- to10-membered nitrogen-containing heterobicyclic group, and mostparticularly, a 5- or 6-membered non-aromatic nitrogen-containingheteromonocyclic group such as pyrrolidinyl, piperazinyl, piperidyl,morpholino, etc., a 5- or 6-membered aromatic nitrogen-containingheteromonocyclic group such as imidazolyl or pyrrolyl, etc., and anitrogen-containing heterobicyclic group such as6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl,5,6,7,8-tetrahydroimidazo[1,2-a]-pyrazin-7-yl,5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl,1,2,3,4-tetrahydro-2-isoquinolinyl,1H-2,3,4,5,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl,4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-6-yl,5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl,4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl, etc.

The nitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is a 5- or6-membered nitrogen-containing heteromonocyclic group or an 8- to10-membered nitrogen-containing heterobicyclic group, for example, a 5-or 6-membered non-aromatic nitrogen-containing heteromonocyclic groupsuch as morpholinyl, piperazinyl, piperidyl, thiadiazolyl,dihydropyrimidinyl, dihydropyrazolyl, a 5- or 6-membered aromaticnitrogen-containing heteromonocyclic group such as pyrimidinyl,pyridazinyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,pyrazinyl, and an 8- to 10-membered nitrogen-containing heterobicyclicgroup such as benzothiazolyl quinolyl, dihydrobenzoxazolyl, etc.

The substituent of the “substituted or unsubstituted nitrogen-containingheterocyclic group” for Ring A and R³, i.e., when thenitrogen-containing heterocyclic group is substituted, is, for example,(1) a lower alkyl group, (2) a hydroxy-substituted lower alkyl group,(3) a formyl group, (4) an oxo group, (5) an amino group, (6) adi-(lower alkyl)amino group, (7) a hydroxy group, (8) a lower alkoxygroup, (9) a lower alkoxycarbonyl group, (10) a lower alkoxy-substitutedlower alkanoyl group, (11) a lower alkanoyl group, (12) acyano-substituted lower alkyl group, or (13) a pyrimidinyl groupsubstituted by (i) a benzylamino group substituted by a halogen atom anda lower alkoxy group and (ii) a cycloalkylcarbamoyl group substituted bya hydroxy group, etc.

The aryl group of the “substituted or unsubstituted aryl group” for R²is, for example, a 5- to 10-membered monocyclic or bicyclic aromatichydrocarbon group such as phenyl group, naphthyl group, etc.

The substituent of the “substituted or unsubstituted aryl group” for R²,when R² is a substituted aryl group, is, for example, a lower alkoxygroup, a halogen atom, a cyano group, a nitro group, a hydroxy group, alower alkyl group, etc.

The substituent of the “substituted or unsubstituted lower alkyl group”for R¹ and the substituent of the “substituted or unsubstitutedcycloalkyl group” for R⁴, i.e., when R¹ and R⁴ are substituted loweralkyl and substituted cycloalkyl, respectively, are, for example, alower alkoxy group, a hydroxy group, a morpholinyl group, a loweralkylsulfonyl group, a di-(lower alkyl)phosphino group, a di-(loweralkyl)amino group, a pyrimidinyl-substituted lower alkylamino group, apyridyl group, a pyridylamino group, a lower alkyl-substitutedpiperazinyl group, a pyrimidinyloxy group, etc.

It should be noted with respect to the above that a “lower alkyl group”refers to a straight chain or branched chain alkyl group having 1 to 6carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, etc., while a “lower alkoxy group” refers to a straightchain or branched chain alkoxy group having 1 to 6 carbon atoms, such asmethoxy, ethoxy, propoxy, isopropyloxy, butyloxy, isobutyloxy,tert-butyloxy, etc.

A “cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbonatoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc. A “lower alkylene group” refers to a straight chain orbranched chain alkylene group having 1 to 6 carbon atoms, such asmethylene, ethylene, trimethylene, etc.

A “halogen” substituent or a “halogen atom” refers to a fluoro, chloro,bromo, or iodo substituent.

Among the compounds (I) of the present invention, preferred compoundsare those wherein the nitrogen-containing heterocyclic group of the“substituted or unsubstituted nitrogen-containing heterocyclic group”for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclicgroup or an 8- to 10-membered nitrogen-containing heterobicyclic group,and the substituent of the above “substituted or unsubstitutednitrogen-containing heterocyclic group” is selected from (1) a loweralkyl group, (2) a hydroxy-substituted lower alkyl group, (3) a formylgroup, (4) an oxo group, (5) an amino group, (6) a hydroxy group, (7) alower alkoxycarbonyl group, and (8) a pyrimidinyl group substituted by(i) a benzylamino group substituted by a halogen atom and a lower alkoxygroup and (ii) a cycloalkylcarbamoyl group substituted by a hydroxygroup, R¹ is a lower alkyl group which may optionally be substituted bya group selected from a lower alkoxy group, a hydroxy group, amorpholinyl group, a lower alkylsulfonyl group, a di-(loweralkyl)phosphino group, a di-(lower alkyl)amino group, apyrimidinyl-substituted lower alkylamino group, a pyridyl group, apyridylamino group, and a lower alkyl-substituted piperazinyl group, agroup of the formula —NH-Q-R³, or a group of the formula —NH—R⁴, thenitrogen-containing heterocyclic group of the “substituted orunsubstituted nitrogen-containing heterocyclic group” for R³ is a 5- or6-membered nitrogen-containing heteromonocyclic group or an 8- to10-membered nitrogen-containing heterobicyclic group, and thesubstituent of the above “substituted or unsubstitutednitrogen-containing heterocyclic group” is selected from a lower alkylgroup, a hydroxy-substituted lower alkyl group, an oxo group, an aminogroup, a di-(lower alkyl)amino group, a lower alkanoyl group and acyano-substituted lower alkyl group, R⁴ is a cycloalkyl groupsubstituted with a group selected from hydroxy, a lower alkoxy, andpyrimidinyloxy, R² is a phenyl group substituted with a group selectedfrom lower alkoxy, a halogen atom, cyano, nitro, hydroxy, and loweralkyl.

Preferred subsets of these compounds are described in U.S. Pat. No.6,656,935 to Yamada et al., the disclosure of which is incorporated byreference in its entirety herein. Avanafil per se, compound (II), isparticularly preferred.

The avanafil is incorporated into the dosage form as a particulatecomposition, with smaller particles preferred to provide increasedsurface area and thus assist in enabling maintenance of a highabsorption rate (as the absorption of avanafil involves primarily apassive diffusion process). Generally, the avanafil particles will havean average diameter in the range of about 5 nm to about 5000 μm, and apreferred range is about 5 μm to about 1000 μm. Particulate avanafil canbe obtained from Tanabe Seiyaku Co., Ltd. (Osaka, JP).

The active agent may be incorporated into the formulations of theinvention as a salt, prodrug, metabolite, analog, isomer, etc., providedthat the salt, prodrug, metabolite, analog, isomer, etc. ispharmaceutically acceptable and, with the exception of prodrugs,pharmacologically active as well. These derivatives may be preparedusing standard procedures known to those of ordinary skill in the artand described, for example, by J. March, Advanced Organic Chemistry:Reaction, Mechanisms, and Structure, 4^(th) edition (New York:Wiley-Interscience, 1992).

For instance, acid addition salts of the active agent can be preparedusing conventional methodology involving the reaction of the free basewith an acid. Suitable acids for preparing acid addition salts includeboth organic acids, e.g., acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like, as well asinorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like. See, for example, U.S.Pat. No. 7,501,409. An acid addition salt may be reconverted to the freebase by treatment with a suitable base. In most embodiments herein,however, it is preferred that the active agent be incorporated into theformulations and dosage forms of the invention as the free base.

Formulations:

The avanafil formulations are adapted for oral drug administration, andare orally disintegrating tablets (also sometimes referred to as“rapidly disintegrating tablets,” as described earlier herein). In orderto improve the absorption of the active agent, the formulations of theinvention contain a absorption enhancing composition, i.e., acomposition selected to reduce precipitation and aggregation of avanafilparticles as the particulate avanafil, dissolved in the stomach, passesinto the far more basic environment of the duodenum. The absorptionenhancing composition thus facilitates greater absorption of theavanafil in the body, in turn making the drug far more effective at agiven dosage. The composition, as noted, preferably is or contains apolymeric component, and preferably is or contains an amphiphiliccomponent, i.e., a component that has at least one hydrophilic segmentand at least one hydrophobic segment, as will be detailed infra. In apreferred embodiment, the absorption enhancing composition comprises anamphiphilic polymer such as a nonionic surfactant.

Suitable absorption enhancing compositions are best selected using asimple and straightforward process as will be described infra. Anycompositions that are pharmaceutically acceptable and which do notadversely interact with the active agent or any other components of theformulation may be used, so long as they are determined to be effectiveaccording to the process described herein. The term “polymeric” is meantto describe preferred component(s) of the absorption enhancingcomposition refers to a molecule containing two or more covalentlyattached monomer units, and includes branched, dendrimeric, and starpolymers as well as linear polymers. The term also includes bothhomopolymers and copolymers, e.g., random copolymers, block copolymers,graft copolymers, and uncrosslinked polymers, as well as slightly,moderately, and substantially crosslinked polymers. Many such suitablecompositions also contain one or more components composed of at leastone hydrophilic segment and at least one lipophilic (hydrophobic)segment, where those terms are used according to their usualdefinitions. See also Aungst, B. J. (2012) AAPS 14(1):P10-18.

Avanafil's solubility profile as a function of pH makes it a transientclass II drug having good solubility in a low pH environment, such asthe stomach, but potentially slow absorption kinetics if the lowsolubility in high pH (greater than 5.0) is the limiting step. An ODTtablet melts quickly in the mouth and is likely fully dissolved in thestomach before the avanafil enters the duodenum where the pH is about6.8. A key parameter is how quickly the dissolved avanafil precipitatesupon entering the duodenum. Slowing the precipitation long enough toallow absorption can be used to achieve the desired pharmacokineticoutcome. Surfactant based formulations may be used to preventaggregation of avanafil particles to reduce precipitation and speedabsorption relative to precipitation since lower surface area leads tofaster absorption kinetics.

Examples of preferred polymeric components that may be incorporated intoor serve as the absorption enhancing composition are thus surfactants.That is, to function as a surfactant, a compound must necessarily beamphiphilic, i.e. include polar or charged hydrophilic moieties, as wellas non-polar lipophilic (hydrophobic) moieties. An empirical parametercommonly used to characterize the relative hydrophilicity andhydrophobicity of non-ionic amphiphilic compounds is thehydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLBvalues are more lipophilic or hydrophobic, and have greater solubilityin oils, while surfactants with higher HLB values are more hydrophilic,and have greater solubility in aqueous solutions. Hydrophilicsurfactants are generally considered to be those compounds having an HLBvalue greater than about 10, as well as anionic, cationic, orzwitterionic compounds for which the HLB scale is not generallyapplicable. Similarly, hydrophobic surfactants are compounds having anHLB value less than about 10. It should be appreciated that the HLBvalue of a surfactant is merely a rough guide generally used to enableformulation of industrial, pharmaceutical and cosmetic emulsions. Formany important surfactants, including several polyethoxylatedsurfactants, it has been reported that HLB values can differ by as muchas about 8 HLB units, depending upon the empirical method chosen todetermine the HLB value; see, e.g., Schott (1990) J. Pharm. Sci.12(1):87-88. Likewise, for certain polypropylene oxide-containing blockcopolymers (e.g., the Pluronic® surfactants, available from BASF Corp.),the HLB values may not accurately reflect the true physical chemicalnature of the compounds. Finally, commercial surfactant products aregenerally not pure compounds, but are complex mixtures of compounds, andthe HLB value reported for a particular compound may more accurately becharacteristic of the commercial product of which the compound is amajor component. Different commercial products having the same primarysurfactant component can, and typically do, have different HLB values.In addition, a certain amount of lot-to-lot variability is expected evenfor a single commercial surfactant product. Keeping these inherentdifficulties in mind, and using HLB values as a guide, one skilled inthe art can readily identify surfactants having suitable hydrophilicityor hydrophobicity for use in the formulations of the present invention.Preferred surfactants herein that are incorporated into or serve as theabsorption enhancing composition generally have an HLB of at least 10,with more preferred surfactants having an HLB of at least 12; thepreferred surfactants herein, and the preferred absorption enhancingcompositions herein, are thus hydrophilic.

Suitable surfactants for use as or in the absorption enhancingcomposition can be anionic, cationic, zwitterionic or non-ionic,although non-ionic surfactants are preferred, particularly non-ionichydrophilic surfactants. Mixtures of surfactants as well as mixtures ofsurfactants with non-surfactant or non-polymeric absorption enhancingcomponents and compositions are also within the scope of the invention.

Surfactants useful herein include, but are not limited to, nonionicsurfactants such as polyethylene glycol fatty acid esters, alcohol-oiltransesterification products, polyglycerized fatty acids, propyleneglycol fatty acid esters, mixtures of propylene glycol fatty acid estersand glycerol fatty acid esters, mono- and diglycerides, sterol andsterol derivatives, sorbitan fatty acid esters and polyethylene glycolsorbitan fatty acid esters, sugar esters, polyethylene glycol alkylethers and polyethylene glycol alkyl phenol ethers,polyoxyethylene-polyoxypropylene block copolymers, and lower alcoholfatty acid esters; and ionic surfactants as will be detailed below.Nonionic surfactants are preferred as or in the absorption enhancingcomposition, and may be either un-ionizable surfactants or ionizablesurfactants that are in un-ionized form. Preferred nonionic surfactants,i.e., un-ionizable surfactants, are as follows:

Polyethylene Glycol Fatty Acid Esters: Although polyethylene glycolitself does not function as a surfactant, a variety of PEG-fatty acidesters, such as PEG-fatty acid monoester, PEG-fatty acid diesters, andPEG-fatty acid mono- and di-ester mixtures have useful surfactantproperties. Among the PEG-fatty acid esters, esters of caproic acid,caprylic acid, capric acid, lauric acid, oleic acid, stearic acid,linoleic acid, and linolenic acid are especially useful.

Alcohol-Oil Transesterification Products: A large number of surfactantsof different degrees of hydrophobicity or hydrophilicity can be preparedby reaction of alcohols or polyalcohols with a variety of natural and/orhydrogenated oils. Most commonly, the oils used are castor oil orhydrogenated castor oil, or an edible vegetable oil such as corn oil,olive oil, peanut oil, palm kernel oil, apricot kernel oil, or almondoil. Preferred alcohols include glycerol, propylene glycol, ethyleneglycol, polyethylene glycol, maltol, sorbitol, and pentaerythritol.Among these alcohol-oil transesterified surfactants, preferredhydrophilic surfactants are PEG-35 castor oil (Incrocas-35), PEG-40hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT® TO),PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil (Crovol A70),PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C-50),PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic/capricglycerides (Labrasol), and PEG-6 caprylic/capric glycerides (Softigen767). Preferred lipophilic surfactants in this class include PEG-5hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9hydrogenated castor oil, PEG-6 corn oil (Labrafil® M 2125 CS), PEG-6almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil (Labrafil® M1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6 peanut oil(Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil (Labrafil® M2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS), PEG-6 triolein(Labrafil® M 2735 CS), PEG-8 corn oil (Labrafil® WL 2609 BS), PEG-20corn glycerides (Crovol M40), and PEG-20 almond glycerides (Crovol A40).

Polyglycerized Fatty Acids: Among the polyglyceryl fatty acid esters,preferred hydrophilic surfactants include polyglyceryl-10 laurate(Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn 1-0), andpolyglyceryl-10 mono, dioleate (Caprol® PEG 860). Preferred lipophilicsurfactants include polyglyceryl oleate (Plurol Oleique), polyglyceryl-2dioleate (Nikkol DGDO), and polyglyceryl-10 trioleate.

Propylene Glycol Fatty Acid Esters: Both mono- and diesters of propyleneglycol may be used. In this surfactant class, preferred lipophilicsurfactants include Capryol 90, Labrafac PG, propylene glycolmonolaurate (Lauroglycol FCC), propylene glycol ricinoleate (Propymuls),propylene glycol monooleate (Myverol P-06), propylene glycoldicaprylate/dicaprate (Captex® 200), and propylene glycol dioctanoate(Captex® 800).

Mono- and Diglycerides: Other suitable surfactants are the mono- anddiglycerides. These surfactants are generally lipophilic. Preferredlipophilic surfactants in this class of compounds include glycerylmonooleate (Peceol), glyceryl ricinoleate, glyceryl laurate, glyceryldilaurate (Capmul® GDL), glyceryl dioleate (Capmul® GDO), glycerylmono/dioleate (Capmul® GMO-K), glyceryl caprylate/caprate (Capmul® MCM),caprylic acid mono/diglycerides (Inmwitor®988), and mono- anddiacetylated monoglycerides (Myvacet® 9-45).

Sterol and Sterol Derivatives: Sterols and derivatives of sterols arecan be hydrophilic or hydrophobic. Preferred derivatives includepolyethylene glycol derivatives, and preferred hydrophilic surfactantsin this class are PEG-24 cholesterol ether (Solulan® C-24), PEG-30cholestanol (Nikkol® DHC), and phytosterol (GENEROL® series, Henkel).

Sorbitan Fatty Acid Esters and Polyethylene Glycol Sorbitan Fatty AcidEsters: A variety of sorbitan esters of fatty acids may be used as or inthe present absorption enhancing composition. Among these esters,preferred hydrophilic surfactants include PEG-sorbitan fatty acidesters, such as PEG-20 sorbitan monolaurate (Tween 20), PEG-20 sorbitanmonopalmitate (Tween 40), PEG-20 sorbitan monostearate (Tween 60), andPEG-20 sorbitan monooleate (Tween 80).

Sugar Esters: Preferred surfactants in this class include sucrosemonolaurate, sucrose monopalmitate, sucrose distearate/monostearate, andsucrose acetate isobutyrate. Examples of commercially available suchsurfactants are the sucrose stearates available as Surfhope® SE D-1803F,D-1805, D-1807, D-1809, D-1811, D-1811F, D-1815, and D-1816 (HLB 3, 5,7, 9, 11, 11, 15, and 16, respectively) from Mitsubishi-Kagaku, sucrosepalmitate available as Surfhope® SE D-1615 and D-1616 (HLB 15 and 16,respectively), and sucrose laurate available as Surfhope® SE D-1216 (HLB16), also from Mitsubishi-Kagaku.

Polyethylene Glycol Alkyl Ethers and Polyethylene Glycol Alkyl PhenolEthers: Ethers of polyethylene glycol and alkyl alcohols or phenols arealso suitable surfactants for use in the present invention. Preferredethers include PEG-3 oleyl ether (Volpo 3), PEG-4 lauryl ether (Brij30), and PEG-10-100 nonyl phenol (Triton X series Rohm & Haas).

Polyoxyethylene-Polyoxypropylene (“POE-POP”) Block Copolymers: ThePOE-POP block copolymers are a unique class of polymeric surfactants.The unique structure of the surfactants, with hydrophilic POE andhydrophobic POP moieties in well-defined ratios and positions, providesa wide variety of surfactants that are suitable herein. Thesesurfactants are available under various trade names, includingSynperonic® PE series (ICI); Pluronic® (series (BASF), Emkalyx®, Lutrol®(BASF), Supronic®, Monolan®, Pluracare®, and Plurodac®. The generic termfor these polymers is “poloxamer” (CAS 9003-11-6). These polymers havethe formula

HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H

wherein “a” and “b” denote the number of polyoxyethylene andpolyoxypropylene units, respectively. All of the poloxamers arechemically similar in terms of their composition, differing only in therelative amounts of propylene oxide and ethylene oxide monomer unitsadded during manufacture and thus incorporated into the final blockcopolymer. Preferred hydrophilic surfactants of this class includePoloxamers 108, 188, 217, 238, 288, 338, and 407. Preferred hydrophobicsurfactants in this class include Poloxamers 124, 182, 183, 212, 331,and 335. Poloxamer 407 is particularly preferred as or in the absorptionenhancing compositions herein. Other block copolymers, particularly ofthe A-B-A type where the A blocks are relatively hydrophobic and the Bblock is relatively hydrophilic can also be used.

Lower Alcohol Fatty Acid Esters: Esters of lower alcohols (C₂ to C₄) andfatty acids (C₈ to C₁₈) are suitable surfactants for use in the presentformulations. Among these esters, preferred hydrophobic surfactantsinclude ethyl oleate (Crodamol EO), isopropyl myristate (Crodamol IPM),and isopropyl palmitate (Crodamol IPP).

Ionizable Surfactants: Ionizable surfactants, when present in neutral,uncharged form, are also nonionic surfactants Particular examples ofsuch surfactants include free fatty acids, particularly C₆-C₂₂ fattyacids, and bile acids. More specifically, suitable unionized ionizablesurfactants include the free fatty acid and bile acid forms of any ofthe fatty acid salts and bile salts. Preferred ionizable surfactantsinclude fatty acids and their corresponding salts, such as caprylicacid/sodium caprylate, oleic acid/sodium oleate, capric acid/sodiumcaprate; ricinoleic acid/sodium ricinoleate, linoleic acid/sodiumlinoleate, and lauric acid/sodium laurate; trihydroxy bile acids andtheir salts, such as cholic acid (natural), glycocholic acid andtaurocholic acid; dihydroxy bile acids and their salts, such asdeoxycholic acid (natural), glycodeoxycholic acid, taurodeoxycholicacid, chenodeoxycholic acid (natural), glycochenodeoxycholic acid,taurochenodeoxycholic acid, ursodeoxycholic acid, tauroursodeoxycholicacid, and glycoursodeoxycholic acid; monohydroxy bile acids and theirsalts, such as lithocholic acid (natural); sulfated bile saltderivatives; sarchocholate; fusidic acid and its derivatives;phospholipids, such as phosphatidyl choline, phosphatidyl ethanolamine,phosphatidyl serine, PD inositol, lysolecithin, and palmitoyllysophosphatidyl choline; carnitines, such as palmitoyl camitine,lauroyl camitine and myristoyl carnitine; cyclodextrins, includingalpha, beta and gamma cyclodextrins; and modified cyclodextrins, such ashydroxypropyl and sulfobutyl ether.

Ionic Surfactants: Ionic surfactants, including cationic, anionic andzwitterionic surfactants, may also be used. Preferred ionic surfactantsinclude fatty acid salts, bile salts, phospholipids, carnitines, ethercarboxylates, succinylated monoglycerides, mono/diacetylated tartaricacid esters of mono- and diglycerides, citric acid esters of mono-,diglycerides, alginate salts, and lactylic esters of fatty acids.Specifically, preferred ionic surfactants include sodium oleate, sodiumlauryl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, sodium cholate, sodium taurocholate, lauroyl carnitine;palmitoyl carnitine; and myristoyl carnitine. It will be appreciated byone skilled in the art, however, that any bioacceptable counterion maybe used. For example, although the fatty acids are shown as sodiumsalts, other cation counterions can also be used, such as alkali metalcations or ammonium. In contrast to typical non-ionic surfactants, theseionic surfactants are generally available as pure compounds.

It should be noted that the rapidly disintegrating tablets of theinvention may be placed on the tongue, or they may be sublingual orbuccal dosage forms. Such dosage forms have significant advantages,particularly for patients who are unable or unwilling to swallow atablet or capsule. The rapidly disintegrating dosage forms herein alsoenable on-demand drug administration that provides for effective bloodlevels of the active agent in a relatively short period of time, anadvantage that is useful with, for instance, erectile dysfunction drugssuch as avanafil to be taken prior to sexual activity.

In addition to the active agent and the absorption enhancingcomposition, the formulation contains a “pharmaceutically acceptablecarrier,” which in the present context generally comprises a pluralityof components, including, typically, at least one binder, at least oneof which is preferably porous, at least one disintegrant, and othercomponents selected from diluents, lubricants, glidants, colorants,flavoring agents, sweeteners, preservatives, and the like.

Binders, also sometimes referred to in the art as granulators, areselected to provide cohesiveness to a dosage form, ensuring that thedosage form, e.g., a tablet, remains intact after preparation viacompaction or the like. Typical binders useful herein include, withoutlimitation, starch; gelatin; waxes; pectins; sugars such as sucrose,glucose, dextrose, molasses, and lactose; gums such as acacia, guar gum,and sodium alginate; polyethylene glycol; hydrophilic polymers such asacrylic acid polymers and copolymers thereof, e.g., those known ascarbomers (Carbopol®, B.F. Goodrich, is one such polymer), polyvinylalcohol, polyvinylpyrrolidone; and cellulosic polymers such ashydroxypropyl methylcellulose (e.g., Methocel®, which may be obtainedfrom the Dow Chemical Company), hydroxypropyl cellulose (e.g., Klucel®,which may also be obtained from Dow), hydroxypropyl cellulose ethers(see, e.g., U.S. Pat. No. 4,704,285 to Alderman), hydroxyethylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose,methyl cellulose, ethyl cellulose, cellulose acetate phthalate,cellulose acetate butyrate, and the like.

As alluded to above, the present formulations preferably include, as asingle binder component or as one of two or more binder components, aporous component that serves to increase bulk density of theformulation, which in turn enables preparation of tablets of greaterhardness than otherwise possible. Hardness, as is understood in the art,is a measure of the cohesiveness of a tablet or other dosage form, andis sometimes equated with tensile strength. Preferred porous bindersherein are directly compressible, water soluble carbohydrates such asmannitol, lactose, sucrose, xylose, trehalose, dextrose, and the like,with directly compressible porous mannitol, porous lactose, and porousglucose particularly preferred. Such components can also serve asdisintegrants and superdisintegrants; see infra.

Disintegrants: Disintegrants are used to facilitate dosage formdisintegration after administration. Typical disintegrants that may beused in conjunction with the present invention include, by way ofexample: starch, starch derivatives such as sodium carboxymethyl starch,pregelatinized starch, and sodium starch glycolate; cellulose andcellulosic materials such as sodium carboxymethylcellulose, other saltsof carboxymethylcellulose, hydroxypropyl cellulose, and crosslinkedcellulosic materials such as crosslinked carboxymethylcelluloses, e.g.,croscarmelose (e.g., Ac-di-Sol®, FMC; U.S. Pat. No. 5,456,921); clayssuch as bentonite; gum and gum-like materials such as alginic acid,sodium alginate, guar gum, Veegum® HV; and other crosslinked materialssuch as cross-linked polyvinylpyrrolidone or “crospovidone” (e.g.,Polyplasdone® XL, GAF).

Preferred disintegrants herein are those commonly referred to as“superdisintegrants,” which facilitate rapid disintegration of thepresent oral dosage forms following introduction into the oral cavity.Superdisintegrants are referred to as such because of their highefficiency, even at low levels (e.g., 2 wt. % to 4 wt. %; seeRemington's, supra). Superdisintegrants are also swellable in water, andthus include numerous swellable crosslinked materials, includingcrosslinked celluloses such as croscarmelose, crosslinked hydrophilicpolymers such as crospovidone, and crosslinked starches such as sodiumstarch glycolate (e.g., available as Explotab® and Explotab CLV®,Penwest Pharmaceuticals Co.). Some materials, as is known in the art,serve multiple functions in oral dosage forms; for instance,microcrystalline cellulose (e.g., Avicel PH1010 and Avicel PH1020, fromFMC; Emocel®, from Edward Mendell Co., Inc.), described in U.S. Pat.Nos. 2,978,446, 3,141,875, and 3,023,104, is useful both as a bindingagent and as a superdisintegrant. Starch-based superdisintegrants usedherein may also be combined with an augmenting agent as described inU.S. Pat. No. 6,660,303 to Staniforth), to increase compactibility ofthe formulation without compromising disintegration kinetics. See also,Mohanachandra et al. 2011 Int. J. of Pharma. Sciences Rev. and Res.6(1):105-109.

Particularly preferred superdisintegrants herein, which can also serveas binders, obviating the need for additional binder components ifdesired, are directly compressible spray dried carbohydrates, such asdirectly compressible mannitol, sorbitol, maltitol, lactose, etc.Directly compressible spray dried mannitol, comprising particles havinga diameter of from about 20 μm to about 200 μm, e.g., from about 50 μmto about 175 μm. The particles are generally crystalline andsubstantially round, and when incorporated into the present formulationin an amount generally in the range of about 30 wt. % to about 90 wt. %,preferably in the range of about 40 wt. % to about 75 wt. %, provide atablet having a porosity corresponding to a bulk density of at least 5.0g/ml. A suitable product for this purpose is that obtainablecommercially as Mannogem™ EZ from SPI Pharma Group and Pearlitol® 200 SDfrom Roquette Incorporated. PEARLITOL® 200 SD is a highly purepreparation of mannitol that can be used to generate tablets of highhardness at low or medium compression forces.

Diluents: Diluents, also termed fillers, are used to increase the bulkof a tablet, so that a practical size is provided for compression.Suitable diluents herein are those generally used in the art, andinclude, for example, dicalcium phosphate dihydrate (e.g., Di-Tab®,Stauffer), sugars that have been processed by cocrystallization withdextrin (e.g., co-crystallized sucrose and dextrin such as Di-Pak®,Amstar), calcium phosphate, cellulose, kaolin, mannitol, lactose,sorbitol, inositol, sodium chloride, dry starch, powdered sugar, and thelike.

Lubricants and glidants: Lubricants are used in the field ofpharmaceutical formulation typically during tablet manufacture, toprevent adhesion of the formulation and its components to the surfacesof the tableting equipment, e.g., punches and dies, and to reduceinterparticle friction, facilitate removal of finished tablets, and toimprove flow during granulation. The quantity of lubricant used istypically in the range of about 0.01 wt. % to about 5 wt. %, preferablyin the range of about 0.01 wt. % to about 1.0 wt. %. Typical lubricantsare stearates such as stearic acid, sodium stearyl fumarate, calciumstearate, zinc stearate, and magnesium stearate, a particularly commonlubricant and useful herein. Other lubricants include hydrogenatedvegetable oils, polyethylene glycol, liquid paraffin, and silicondioxide. Glidants are useful herein when the formulation is preparedusing a dry granulation or direct compression technique, to improve flowcharacteristics of a dry mixture. Colloidal silica (e.g., Cab-O-Sil®,Cabot) and talc are commonly used glidants and are useful in conjunctionwith the present invention. It should be noted that talc may serve asboth a lubricant and a glidant.

Colorants: A colorant must be added if a colored formulation or dosageform is desired. Suitable colorants include natural colorants, i.e.,pigments and dyes obtained from mineral, plant, and animal sources.Examples of natural colorants include red ferric oxide, yellow ferricoxide, annattenes, alizarin, indigo, rutin, and quercetin. Syntheticcolorants may also be used, and will typically be an FD&C or D&C dye,e.g., an approved dye selected from the so-called “coal-tar” dyes, suchas a nitroso dye, a nitro dye, an azo dye, an oxazine, a thiazine, apyrazolone, a xanthene, an indigoid, an anthraquinone, an acridine, arosaniline, a phthalein, a quinoline, or a “lake” thereof, i.e., analuminum or calcium salt thereof. Particularly preferred colorants arefood colorants in the “GRAS” (Generally Regarded As Safe) category.Particularly preferred colorants are also water soluble. In preparingthe present formulations, colorant(s) are typically added to thepharmaceutical mixture prior to the granulating process. Since colorantscan occasionally migrate during wet granulation and result in unevencoloring of the final dosage form, additives that mitigate againstmigration can be incorporated into the formulation e.g., tragacanth,acacia, talc, attapulgite, and the like. Migration of colorant duringwet formulation can also be reduced by drying the granulation slowly atlower temperatures and stirring the granulation as it dries.

Sweeteners and flavoring agents: In order to enhance the taste of thedosage form, at least one sweetener is preferably incorporated into theformulation or dosage form. The sweetener may be a sugar, e.g., sucrose,fructose, or dextrose, or, more preferably, a non-sugar sweetening agentto reduce both caloric intake and the likelihood of dental caries.Sweeteners falling within the latter group include many well knownartificial sweetening agents, such as, for instance, aspartame,saccharin, saccharin salts (e.g., sodium saccharin, calcium saccharin),sucralose, acesulfame potassium, neotame, sorbitol, xylitol, stevioside,steviol, mannitol, erythritol, lactitol, maltitol, alitame,neohesperitin dihydrochalcone, glucin, miraculin, monellin, andthaumatin. In lozenges of the invention, the sweetener is generallyincorporated within the wet matrix, i.e., physically entrapped therein,while when the dosage form is a gum, this is not generally the case.Flavoring agents can be natural, artificial, or a combination thereof.Examples of suitable flavoring agents are flavor oils such as such asspearmint oil, peppermint oil, clove oil, cinnamon oil, citrus oils(e.g., lemon, lime, orange) and synthetic organics such as certainaldehydes and esters, e.g., cinnamyl acetate, cinnamaldehyde, citraldiethylacetal, and the like. Flavorants may be used to provide for tastemasking if one or more of the components render the formulation ordosage form bitter-tasting or otherwise unpleasant in taste, or maysimply enhance a neutral flavor.

Coating: A tablet dosage form of the invention may be coated with one ormore layers of membrane coating materials for sealing purposes, as isknown in the art. An outer coating may also include one or morecolorants to provide a colored dosage form as desired and/or to improvethe taste of the tablet. These coatings may be sugar coatings, filmcoatings, color coatings, or the like.

The present formulations may also include a transmucosal absorptionenhancer to facilitate permeation through the mucosal surfaces of theoral cavity. Such enhancers are known to those of skill in the art ofpharmaceutical formulation, and/or are described in the pertinent textsand literature. Many such transmucosal absorption enhancers are gels.Specific examples of suitable transmucosal absorption enhancers include,without limitation, poloxamers, polyvinyl alcohol, polyethylene glycol,propylene glycol, fatty acid mono- and di-esters of glycerol (e.g.,propylene glycol monolaurate), and fatty acid esters of polyethyleneglycol (e.g., polyethylene glycol monolaurate).

The dosage forms herein, e.g., orally disintegrating tablets, can be ofany suitable size and shape, and the invention is not limited in thisregard. That is, the dosage forms may be, for instance, triangular,round, rectangular, square, biconvex, multilayered, or have an irregularshape. There may also be letters or characters embossed or printed onthe dosage form surface.

The formulations of the invention can also be adapted for sublingual orbuccal administration. In the former case, somewhat smaller and/orflatter dosage forms may be desirable, e.g., a thin film, or an orallydisintegrable dosage form as otherwise provided herein may sufficewithout modifications made to size or shape. For buccal administration,the dosage form may be a tablet or film and will adhere to the oralmucosa, e.g., the gum, and, for that purpose, will contain at least onecomponent that facilitates adhesion to the buccal mucosa until drugrelease and/or dosage form disintegration (which preferably occurroughly simultaneously) are complete. Such components are typicallyhydrophilic, water-swellable polymers that adhere to the wet surface ofthe buccal mucosa and include, for instance, e.g., carbomers, hydrolyzedpolyvinylalcohol, polyethylene oxides, polyacrylates, and the like. Forbuccal administration the drug, or some portion thereof, diffusesthrough the oral mucosa and enters directly into the bloodstream. See,e.g., U.S. Pat. No. 6,284,262 to Place, U.S. Pat. Nos. 6,548,490,7,927,623 and 8,613,950. Avanafil is a BCS-2B drug, characterized byhigh permeability, relatively poor solubility at neutral and high pH andgood solubility at low pH, making it suitable for buccal delivery.

Dissolvable oral thin films (OTFs) may be used for delivery of avanafil.Dissolvable films are often composed of an aqueous polymer matrix.Dissolvable film employed in buccal systems may be designed asbioerodable mono-or multi-layers systems and may feature a mucoadhesivetailored for the desired dwell time. Bioerodible systems offer patientsthe convenience of rapid onset and complete system disintegration. Thesize of the film may be, for example, about 4 to 10 cm² with a depth of0.1 to 4 mm. The dimensions of the film will be proportionate to thedose of the active agent, e.g. larger doses requiring larger films.

In another aspect, avanafil is provided in an oral formulation usingamorphous dispersions that may be made by hot-melt extrusion involvingco-melting of the drug substance and an appropriate polymeric excipient.The active agent may also be micronized or formed into nanocrystalsprior to incorporation into a film, gel or tablet dosage form.

In addition, the formulations and dosage forms herein may be madeeffervescent using components and techniques known to those of ordinaryskill in the art and/or described in the pertinent texts and literature.See, e.g., Remington: The Science and Practice of Pharmacy, NineteenthEdition, cited previously. For example, prior to compaction, andpreferably during the initial phase of formulation, sodium bicarbonateand either citric acid, tartaric acid, or sodium bisphosphate areblended into the mixture so as to become incorporated into the finalproduct. On contact with water, i.e., in the oral cavity, carbon dioxideis released as a result of the acid-base reaction that occurs; theeffervescence serves to at least partially taste mask any unpleasanttaste associated with one or more components in the dosage form orformulation, e.g., that of the active agent itself.

Taste masking may also be accomplished in other ways, as noted above,e.g., using sweeteners and flavoring agents as described above, otherflavoring agents, or by coating the dosage form with one or morecoatings effective to provide taste masking, as is known in the art.

Methods of Use:

The formulations and dosage forms of the invention may be used to treatany adverse condition, disease or disorder that are generally treatablewith a Type V phosphodiesterase inhibitor (PDE V inhibitor). Thepharmacological and physiological mechanisms and effects of PDE Vinhibitors suggest the utility of these agents in treating a variety ofconditions, diseases and disorders in which modulation of smooth muscle,renal, hemostatic, inflammatory, and/or endocrine function is desirable.Adverse conditions, diseases, and disorders treatable by PDE Vinhibitors and thus treatable using the formulations and dosage forms ofthe invention include, but are not limited to, erectile dysfunction,premature ejaculation, female sexual dysfunction, cardiovascular,cerebral stroke, congestive heart failure, cerebrovascular conditions,ischemic heart disease, pulmonary arterial hypertension, acuterespiratory distress syndrome, benign prostatic hypertrophy,atherosclerosis, autoimmune diseases, overactive bladder, bladder outletobstruction, incontinence, cachexia, cancer, diabetes, endarterectomy,diseases characterized by disorders of gut motility, dysmenorrhoea,elevated intraocular pressure, glaucoma, glomerular renal insufficiency,hyperglycemia, hypertension, impaired glucose tolerance, inflammatorydiseases, insulin resistance syndrome, intestinal motility, maculardegeneration, nephritis, optic neuropathy, osteoporosis, peripheralarterial disease, polycystic ovarian syndrome, renal failure,respiratory tract disorders, thrombocytemia, tubular interstitialdiseases, and urologic disorders. Urological disorders include femaleand male sexual dysfunctions.

Allergic disorders include, but are not limited to, urticaria, eczema,and rhinitis.

Cardiovascular diseases include, but are not limited to,atherosclerosis, restenosis, hypertension, acute coronary syndrome,angina pectoris, arrhythmia, a cardiovascular disease associated withhormone replacement therapy, cerebral infarction, cerebral ischemia,conditions of reduced blood vessel patency (e.g., postpercutaneoustransluminal coronary or carotid angioplasty, or post-bypass surgerygraft stenosis), deep vein thrombosis, disseminated intravascularcoagulation syndrome, heart disease, heart failure, migraine, myocardialinfarction, peripheral vascular disease, Raynaud's disease, renalischemia, renal vascular homeostasis, thrombotic or thromboembolyticstroke, venous thromboembolism, pulmonary arterial hypertension,congestive heart failure, myocardial infarction and angina, andprevention of any such cardiovascular condition or event subsequent to afirst cardiovascular event (i.e., “secondary prevention”).

Diseases characterized by disorders of gut motility include, but are notlimited to, irritable bowel syndrome, diabetic gastroparesis anddyspepsia.

Female sexual dysfunction (FSD) includes, but is not limited to,clitoral dysfunction, female hypoactive sexual desire disorder, femalesexual arousal disorder (FSAD), female sexual pain disorder, and femalesexual orgasmic dysfunction (FSOD).

Respiratory tract disorders include, but are not limited to, acuterespiratory failure, allergic asthma, allergic rhinitis, bronchitis,chronic asthma, reversible airway obstruction, and allergic disordersassociated with atopy (such as urticaria, eczema, or rhinitis).

Other medical conditions for which a PDE V inhibitor is indicated, andfor which treatment with the formulations of the present invention maybe useful include, but are not limited to, pre-eclampsia, Kawasaki'ssyndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy,neuropathy including autonomic and peripheral neuropathy and inparticular diabetic neuropathy and symptoms thereof (e.g.,gastroparesis, peripheral diabetic neuropathy), Alzheimer's disease,psoriasis, skin necrosis, metastasis, baldness, nutcracker oesophagus,anal fissure, hemorrhoids, insulin resistance syndrome, hypoxicvasoconstriction as well as the stabilization of blood pressure duringhemodialysis.

Preferably, the diseases treated using the formulations of the inventioninclude erectile dysfunction, pulmonary arterial hypertension,congestive heart failure, benign prostatic hypertrophy, myocardialinfarction and angina.

Often, the formulations and dosage forms of the invention will beprescribed for and used in the prevention and treatment of erectiledysfunction. As explained in U.S. Pat. No. 6,403,597 to Wilson et al.,rapid release dosage forms such as those provided herein are uniquelysuited to as-needed administration prior to sexual activity.

Avanafil may be provided in a daily dose ranging from 10 mg to 800 mg.Exemplary doses may be 50 mg, 100 mg or 200 mg. For most patients astarting dose of 100 mg may be taken 15 to 30 minutes before sexualactivity on an as needed basis. Avanafil taken in tablet form is rapidlyabsorbed after oral administration, with a median Tmax of 30 to 45minutes in the fasted state. When 100 mg or 200 mg is taken with a highfat meal, the rate of absorption is reduced, with a mean delay in Tmaxof 1.12 to 1.25 hours and a mean reduction in Cmax of 24% (100 mg) and39% (200 mg). There was an approximate 3.8% decrease in AUC. The smallchanges in avanafil Cmax and AUC are considered of minimal clinicalsignificance; therefore, avanfil may be administered with or withoutfood. Avanafil is cleared predominantly by hepatic metabolism, mainly bythe CYP3A4 enzyme and to a minor extent by CYP2C isoform. The plasmaconcentrations of the major circulating metabolites, M4 and M16, areapproximately 23% and 29% that of the parent compound, respectively. TheM4 metabolite has an in vitro inhibitory potency for PDES 18% of that ofavanafil and M4 accounts for approximately 4% of the pharmacologicactivity of avanafil. The M16 metabolite was inactive against PDES.

Method of Manufacture:

Formulations and dosage forms of the invention may be prepared usingconventional techniques used in the fabrication of oral drugpreparations, e.g., direct compression, roller compaction, drygranulation, or wet granulation. In one aspect of the invention, a newand particularly effective technique is provided for preparing thepreferred rapidly disintegrating oral avanafil dosage forms describedherein, such that absorption is increased despite the fact that avanafiland its analogs are poorly soluble at the typical pH of the duodenum.The new technique may employ any of the aforementioned dosage formpreparation methods, i.e., direct compression, dry granulation, or wetgranulation. The novel method of manufacturing, while an optimal processfor formulating the dosage forms described and claimed herein, may beused to manufacture orally disintegrating tablets in general, i.e., withother active agents and the like, and may not always employ anabsorption enhancing composition.

In direct compression and roller compaction, the particulate material tobe included in the dosage form is compressed in a tablet press orsubjected to compaction in a roller mill directly. Dry granulation, asis known in the art, may be utilized effectively when at least one ofthe formulation components has sufficient cohesive properties to betableted. Wet granulation involves mixing the components that willcomprise the dosage form in a blender, e.g., a twin shell blender or adouble-cone blender, and thereafter adding solutions of additionalcomponent(s), including at least one binding agent, to obtain agranulation. The damp mass is then screened using a sieve withpre-defined mesh sizes followed by drying with a fluid bed dryer, aspray dryer, vacuum, or the like. Additional information and detailsconcerning these processes are described at length in the pertinenttexts and literature, and will in any case be known to those of ordinaryskill in the art of pharmaceutical formulation.

The manufacturing method of the invention involves a multi-step processin which the mixture of components that will be incorporated into thefinal oral dosage form is divided and separately processed. Inparticular, the method involves: an initial step in which a fraction,i.e., some but not all, of the formulation used to prepare the dosageform, is mixed, process in a manner to provide particles or granules,and dried; a second step in which the remainder of the formulation isblended in; and, finally, compaction of the entire mixture using atablet press or other compression technique, to prepare the rapidlydisintegrating oral dosage form. Generally, the first two steps involvedry or wet granulation, although, as noted, other techniques may beused. Preferably, the first fraction of the formulation contains activeagent, a disintegrant, e.g., a superdisintegrant, a porous binder, andoptionally one or more additional binders, such that the initial step ofthe process provides active agent granules, while the remainder of theformulation that is later blended in contains a lubricant, additionaldisintegrant, and additional porous binder. The steps, i.e., the initialstep as well as the second step, are, as noted, preferably granulationsteps, and most preferably are carried out using wet granulationtechniques and equipment.

In a preferred embodiment, all of the active agent is subject togranulation in the initial step of the process, such that prior to thesecond step, active agent granules are prepared and dried. When anabsorption enhancing composition is employed, it is preferred that allof that composition is incorporated in the initial step as well, suchthat the active agent and absorption enhancing composition areintimately admixed prior to further processing. It is also preferredthat any lubricant be added in only the second step, while the porousbinder be added in only the second step or in both steps. Dividing thetotal amount of porous binder in this way reduces the likelihood thatthe component will collapse and lose its ability to dissolve quickly, ascan happen with porous superdisintegrants that can serve as binders inrapidly disintegrating dosage forms. The porous binder, e.g., porousmannitol, may be divided in an approximately 50-50 manner, althoughgenerally the ratio of porous binder incorporated in the initial step tothe porous binder in the second step may be anywhere from about 5:1 to1:5, preferably 3:1 to 1:3, and most preferably 2:1 to 1:2.

The relative amounts of the components in the composition is as follows,based on the percentage by weight of the final dried dosage form: activeagent, about 10% to about 50%; porous binder/superdisintegrant (e.g., adirectly compressible carbohydrate such as porous mannitol), about 30%to about 85%, preferably about 40% to about 75%; lubricant, about 0.01%to about 3.0%, preferably in the range of about 0.01% to about 1.0%;other components such as colorants, sweeteners, flavoring agents, etc.,0% to about 5%, preferably 0.1% to about 5%. When an absorptionenhancing composition is used, the active agent and absorption enhancingcomposition will generally although not necessarily together representabout 10 wt. % to 70 wt. % of the final dosage form, with the activeagent and absorption enhancing composition generally in a ratio in therange of about 10:1 to about 1:5.

Manufacturing the formulations and dosage forms of the invention in thisway significantly enhances the competing physical properties mostdesired in a rapidly disintegrating tablet: on the one hand, physicalintegrity, as represented by the tablets' hardness, in turn enabled byachieving a high bulk density; and, on the other hand, rapiddisintegration time, because of the significant amount of porous binderthat can be incorporated in the multi-step method. For instance, usingthe above-mentioned technique, oral dosage forms can be prepared whichdisintegrate within the oral cavity within about 45 seconds and exhibita hardness of greater than about 30 N. Preferred oral dosage formsherein disintegrate within the oral cavity within about 30 seconds andexhibit a hardness of greater than about 15 N, and most preferred oraldosage forms prepared using the present method disintegrate within theoral cavity within about 15 seconds and exhibit a hardness of greaterthan about 7.5 N.

Method for Selecting Compositions to Enhance Duodenal Absorption:

The invention also provides a method for evaluating and selecting acompound or combination of compounds that will enhance the absorption ofavanafil in the duodenum by reducing precipitation and/or aggregation ofthe active agent upon leaving the stomach and entering the higher pHenvironment of the duodenum. The method used involves a photometricanalysis in which the amount of light transmitted by a compositioncontaining the active agent and a candidate composition is measured as afunction of time, with decreasing transmission indicative ofprecipitation and/or aggregation. Selection criteria involve factorssuch as aggregation onset time, transmission lowering rate, andasymptotic transmission.

The photometric method is carried out as follows. A known quantity of acandidate compound or composition, i.e., a compound or compositionundergoing evaluation as a potential absorption enhancing compositionherein, is dissolved in water that has been acidified to a pH of about2.5, thereby approximating the pH of the stomach. After dissolution iscomplete, as may be monitored visually, the pH of the solution isincreased to about 7.0, to approximate the pH of the duodenum. This maybe done with any suitable basifying agent. As soon as a pH of 7.0 isreached, a source of light (e.g., an HeNe laser) is turned on anddirected into the solution, and transmission measurements are made atregular time intervals, e.g., every ten seconds, every twenty seconds,every thirty seconds, etc., up to at least thirty minutes. Normalizedtransmission values—i.e., the fraction of the transmission seen at time“zero,” when the active agent is in solution—is evaluated at each timepoint, and the results plotted, as done in Example 2. Results arecompared with a control experiment using only the active agent withoutany candidate component or composition present.

A candidate compound or composition was determined to “reduce theprecipitation and/or aggregation” of avanafil upon titration of thesolution to pH 7.0 if the compound was found to (1) delay the onset ofavanafil precipitation at pH 7.0, (2) prolong the time period duringwhich avanafil precipitates following titration of the avanafil solutionto 7.0, (3) delay the start of the process in which precipitatedavanafil is visually observed to form aggregates, or (4) prolong thetime period during which precipitated avanafil was observed to formaggregates. Among many successful such candidates and compounds are thepoloxamers, i.e., polyoxyethylene-polyoxypropylene block copolymers, asdescribed in detail earlier herein.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof that theforegoing description as well as the examples that follow are intendedto illustrate and not limit the scope of the invention.

Example 1

A high performance liquid chromatography (HPLC) procedure was used toevaluate the aqueous solubility of avanafil (obtained from TanabeSeiyaku Co., LTD, purity, 97.0% to 103% with an observed purity of98.89%; particle diameter, 10-20 microns with median observed particlediameter of 18.47 microns) at a range of pH values. The HPLC conditionswere as follows: system, HP Model 1100; analytical column, SupelcoKromasil C8, 4.6 mm×250 mm, 5 μm particle size; assay injection volume,20 μl; stock stability injection volume, 0.5 μl; needle wash volume, 91μl; mobile phase flow rate, 1.00 ml/minute; column temperature, 30° C.;detection wavelength 246 nm; flow cell path length, 10 mm; range step2.00 nm; threshold, 1.00 mAU; stop time, 30 minutes. The results arepresented in Table 1. Solutions 1, 2, 3, 6, 7, 8, 11, and 12 werebuffered to pH values of 0.99, 2.00, 3.00, 6.00, 7.00, 8.00, 11.0, and12.0, respectively, using a phosphate buffer, 0.1M KH₂PO₄. Solutions 4and 5 were buffered to pH values of 4.00 and 5.00, respectively, using asodium acetate buffer, 0.1M NaOAc, while solutions 9 and 10 wererespectively buffered to pH values of 9.00 and 10.00 using a sodiumcarbonate buffer, 0.1M Na₂CO₃.

TABLE 1 Solution Buffer Solution pH Solubility, μl/ml ASTM Type II H₂ONone — 0.139 Solution 1 0.1M KH₂PO₄ 0.999 >199,000 Solution 2 0.1MKH₂PO₄ 2.00 35,000 Solution 3 0.1M KH₂PO₄ 3.00 1,700 Solution 4 0.1MNaOAc 4.00 344 Solution 5 0.1M NaOAc 5.00 19.5 Solution 6 0.1M KH₂PO₄6.00 1.28 Solution 7 0.1M KH₂PO₄ 7.00 0.233 Solution 8 0.1M KH₂PO₄ 8.000.0520 Solution 9 0.1M Na₂CO₃ 9.00 <0.0500 Solution 10 0.1N Na₂CO₃ 10.0<0.0500 Solution 11 0.1M KH₂PO₄ 11.0 0.0568 Solution 12 0.1M KH₂PO₄ 12.0<0.0500

As expected, the solubility of avanafil markedly decreased withincreasing pH, evidencing solubilities of 35,000 μl/ml at a pH of 2.00,1,700 μl/ml at a pH of 3.00, and 0.233 μl/ml at a pH of 7.00. The lattervalue represents the solubility of avanafil at the approximate pH of theduodenum, while the solubility of avanafil in the stomach will normallyfall between the first two values, as the pH in the average stomach isapproximately 2.5.

Example 2

Various compounds were evaluated for their ability to increase theaqueous solubility of avanafil at an elevated pH by reducing theprecipitation and/or aggregation of avanafil following titration of anaqueous solution of avanafil at pH 2.5 to a pH of 7.0, as follows.

Avanafil, 33.3 mg, and 13.3 mg of the compound(s) to be evaluated wereweighed out and added to 300 ml of DI water in a beaker. Mixing wascarried out using a magnetic stirrer at low speed, approximately 50 rpmto 100 rpm. Hydrochloric acid, 0.2M, was gradually added until a pH of2.5 was reached; this pH was selected as the starting point for theevaluation since it is the average pH of the stomach. Mixing wascontinued for a short time to ensure dissolution of the avanafil and thecompound(s) being evaluated.

Then, sodium hydroxide was gradually added to raise the pH toapproximately 7.0, the average pH of the duodenum. As soon as a pH of7.0 was reached, an HeNe laser was turned on and transmitted into thesolution in the beaker. The transmission as a function of time wasmeasured and photographs of the solution were taken at regularintervals, until the transmission was lowered by at least a factor often. At this point, the laser was turned off and the solution wasallowed to sit for at least 30 minutes, to observe the end state of theexperiment. Turbidity was also determined, by evaluating the differencebetween the scattered light and the transmitted light at eachmeasurement interval.

Each compound evaluated was determined to be a promising candidate forincorporation into an avanafil ODT if the compound increased thesolubility of avanafil at pH 7.0, as determined from the opticalmeasurement(s) made at the 30-minute point, and/or reduced theprecipitation and/or aggregation of avanafil following titration of theaqueous avanafil solution from pH 2.5 to a pH of 7.0. A compound wasdetermined to “reduce the precipitation and/or aggregation” of avanafilupon titration of the solution to pH 7.0 if the compound was found to(1) delay the onset of avanafil precipitation at pH 7.0, (2) prolong thetime period during which avanafil precipitates following titration ofthe avanafil solution to 7.0, (3) delay the start of the process inwhich precipitated avanafil is visually observed to form aggregates, or(4) prolong the time period during which precipitated avanafil wasobserved to form aggregates.

A control experiment was also run using 46.6 mg avanafil in 300 ml DIwater without any additional compounds present.

The compounds evaluated using the aforementioned procedures were asfollows: Fumaric acid; Polyvinyl alcohol (PVA); Tween 20; Tween 80;Tween 80/Span 20 in a 6:4 wt. ratio; Tween 80/Span 20 in a 6:4 wt ratiowith PVA; Tween 80/ascorbic acid mixture; Sodium dodecyl sulfate (SDS);Poloxamer 188; Poloxamer 407; TPGS; Polyethylene glycol 200;Polyethylene glycol 400; Polyethylene glycol 600; Polyethylene glycol1000; Polyethylene glycol 3500; Sodium lauryl sulfate (SLS); Stearylalcohol; Steric acid; Sodium acetate; Sucrose palmitate (SE D-1616,Mitsubishi); and Sucrose stearate (SE D-1815, Mitsubishi).

For each of these candidate compound(s), normalized transmissionfraction (i.e., measured transmission as a fraction of an initialtransmission set equal to 1.0) was plotted versus time. The results forthe control solution, containing avanafil without an added candidatecompound are shown in FIG. 1 and the results for sucrose palmitate,SE1616, are shown in FIG. 2. Turbidity (FTU) measurements that were madeare plotted in FIG. 3 for the control and in FIG. 4 for sucrosepalmitate.

Example 3

A tablet containing about 50% avanafil was made using a method thatincluded a first mixing step where approximately half the total amountof PVP and magnesium stearate was added prior to granulation and theremaining PVP and magnesium stearate was added after granulation.

Ingredient Composition (%) Avanafil 50.02 (Lot: 17AP303020) Pearlitol200 SD 37.13 (Roquette, Lot: E233P) XL-10 PVP 3.94 (ISP, lot:3600163932) Pepper Mint 6.19 (Adams Extract, exp: 6 Sep. 2009) Ascorbicacid 0.22 (Science Lab: Lot: SLA1972) Magnesium Stearate dihydrus 2.09(Tyco-Mallinkrodt; Lot: J03970) Color-LB-1587 Green 0.27 (Colorcon LotTS 045675) Ace K 0.13 (Premium ingredients international; Lot: 20080131)Neotame 0.01 (NutraSweet Company; Lot: B604066256)

Process: Mix 50% of the ISP PVP XL-10 with all other ingredients exceptMagnesium Stearate dihydrus at room temperature. Roller compact themixture. Granulate the compacted ribbons by passing through Mesh 20sieving screen. Add the remaining 50% of PVP XL-10 and MagnesiumStearate dihydrus to the screened granules. Tablet press and measurehardness (13.5N). Measure disintegration time (oral test: 7 seconds).

Example 4

A tablet containing about 34% avanafil was made using a method thatincluded a first mixing step where approximately half the total amountof PVP and magnesium stearate was added prior to granulation and theremaining PVP and magnesium stearate was added after granulation.

Ingredient Composition (%) Avanafil 34.30 (Lot: 17AP303020) Pearlitol200 SD 48.90 (Roquette, Lot: E233P) XL-10 PVP 5.21 (ISP, lot:3600163932) Pepper Mint 8.15 (Adams Extract, exp: 6 Sep. 2009) Ascorbicacid 0.19 (Science Lab: Lot: SLA1972) Magnesium Stearate dihydrus 2.72(Tyco-Mallinkrodt; Lot: J03970) Color-LB-1587 Green 0.34 (Colorcon LotTS 045675) Ace K 0.17 (Premium ingredients international; Lot: 20080131)Neotame 0.02 (NutraSweet Company; Lot: B604066256)

Process: Mix 50% of the ISP PVP XL-10 with all other ingredients exceptMagnesium Stearate dihydrus at room temperature. Roller compact themixture. Granulate the compacted ribbons by passing through Mesh 20sieving screen. Add the remaining 50% of PVP XL-10 and MagnesiumStearate dihydrus to the screened granules. Tablet press and measurehardness (19.7N). Measure disintegration time (oral test: 16 seconds).

Example 5

Formulation with Fumaric Acid.

Ingredient Composition (%) Avanafil 40.40 (Lot: 17AP303020) Pearlitol200 SD 50.50 (Roquette, Lot: E233P) Fumaric Acid 1.80 XL-10 PVP 4.50(ISP, lot: 3600163932) Magnesium Stearate dihydrus 2.50(Tyco-Mallinkrodt; Lot: J03970) Ace K 0.30 (Premium ingredientsinternational; Lot: 20080131)

Process: Weigh 4 gm avanafil in a jar. Weigh 5 gm of Pearlitol 200 SD ina separate jar. Add 1.8 gm of fumaric acid solution (pH=1.98) to theavanafil jar and mix well. When avanafil is fully mixed, add the 5 gm ofPearlitol 200 SD from the other jar to the avanafil/fumaric acid jar andmix well. Add Ace K. Wet granulate through a mesh=18 curved screen anddry at 65° C. for 1 hr. Add magnesium stearate and X1-10 PVP. Check bulkdensity, flowability; add lubricant if necessary. Tablet press and checkhardness (40-60 N) and friability (<1%). Measure disintegration time(USP 701: 25 seconds; oral test: 12 seconds).

Example 6

Formulation with added surfactant. As an example of a formulation wherea surfactant was added to improve solubility at neutral pH, Tween80/Span 20 was used.

Ingredient Composition (%) Avanafil 34.13% (Lot: 17AP303020) Pearlitol200 SD 42.68% (Roquette, Lot: E233P) X-10 PVP 4.88% (ISP, lot:3600163932) Magnesium Stearate dihydrate 7.74% (Tyco-Mallinkrodt; Lot:J03970) Tween 80/Span 20 (6:4) 8.53% Ace K (Premium ingredients 2.04%international; Lot: 20080131)

Process: Weigh 4 gm avanafil in a jar. Add 0.6 gm of Tween 80/Span 20(6:4) to the Avanafil jar. Then add 0.7 ml deionized water to the jar.Wet granulate the mixture and pass through a 30 mesh screen, then dry inambient temperature overnight. Sieve through the 30 mesh screen againand check bulk density and flowability. Add Pearlitol 200 SD and Ace K.Tablet press and measure hardness (40-60 N) and disintegration time(oral: 15 seconds).

We claim:
 1. An orally disintegrating tablet, comprising the following:a therapeutically effective amount of avanafil; an absorption enhancingcomposition comprising a surfactant; an orally disintegratingcomposition comprising a disintegrant; and a porous component in apharmaceutically acceptable carrier.
 2. The tablet according to claim 1,wherein the tablet disintegrates within the oral cavity within about 45seconds and exhibits a hardness of greater than about 30 N.
 3. Thetablet according to claim 2, wherein the tablet disintegrates within theoral cavity within about 30 seconds and exhibits a hardness of greaterthan about 15 N.
 4. The tablet according to claim 2, wherein the tabletdisintegrates within the oral cavity within about 15 seconds andexhibits a hardness of greater than about 7.5 N.
 5. The tablet accordingto claim 1, wherein the disintegrant is a superdisintegrant.
 6. Thetablet according to claim 1, wherein the porous component comprisesporous mannitol.
 7. The tablet according to claim 1, wherein thesurfactant comprises a polymeric component that mitigates theprecipitation of avanafil in an aqueous medium as pH increases fromabout 2.5 to about 7.0.
 8. The tablet according to claim 7, wherein thepolymeric component is nonionic and mitigates the precipitation ofavanafil in an aqueous medium as pH increases from about 2.5 to about7.0 by delaying precipitation, reducing the rate of precipitation,decreasing the extent of precipitation, or any combination of theforegoing.
 9. The tablet of claim 8, wherein the polymeric component iscomprised of a hydrophilic segment and a hydrophobic segment.
 10. Thetablet according to claim 8, wherein the polymeric component iscomprised of a polyoxyethylene-polyoxypropylene copolymer.
 11. Thetablet according to claim 10, wherein the polymeric component comprisespoloxamer
 407. 12. The tablet according to claim 1, wherein the avanafilrepresents in the range of about 10 wt. % to about 50 wt. % of thetablet.
 13. The tablet according to claim 12, wherein the avanafilrepresents up to about 70 wt. % of the dosage form.
 14. The tabletaccording to claim 1 wherein the tablet does not comprise fumaric acid,tartaric acid, succinic acid, malic acid, ascorbic acid or asparticacid.
 15. A method for administering a PDE V inhibitor to a subjecthaving a PDE V inhibitor-treatable condition selected from erectiledysfunction, hypertension, angina pectoris, myocardial infarction, heartfailure, pulmonary arterial hypertension, prostatic hyperplasia, femalesexual dysfunction, neurogenesis, neuropathy, Alzheimer's disease,psoriasis, skin necrosis, metastasis, baldness, nutcracker oesophagus,anal fissure, hemorrhoids, insulin resistance syndrome, hypoxicvasoconstriction, and blood pressure stabilization, comprising orallyadministering the tablet according to claim 1 to the subject on anas-needed basis.
 16. A method for manufacturing a rapidly disintegratingoral dosage form, comprising: (a) preparing active agent granules by (i)blending a pharmacologically active agent in particulate form with afirst fraction of a disintegrant and a first fraction of a porousbinder, to form an initial mixture, and (ii) granulating the initialmixture for a predetermined time period at a predetermined temperature,to provide the active agent granules; (b) blending the active agentgranules with a lubricant, a second fraction of a disintegrant, and asecond fraction of a porous binder, to provide a final formulationmixture; and (c) compacting the final formulation mixture to prepare therapidly disintegrating oral dosage form.
 17. The method of claim 16,wherein granulating is carried out in a solvent and step (a) furthercomprises drying the granulation prepared in (ii) prior to step (b). 18.The method of claim 16, wherein the porous binder is selected fromporous mannitol, porous lactose, and porous glucose and wherein thedisintegrant comprises at least one superdisintegrant.
 19. The method ofclaim 17, wherein the active agent is avanafil and the method furthercomprises incorporating an absorption enhancing composition into thedosage form, wherein a first fraction of the absorption enhancingcomposition is incorporated in (a) and a second fraction of theabsorption enhancing composition is incorporated in (b).
 20. An orallydisintegrating tablet having hardness of 13.5 N or more, which isobtained by a process comprising the following steps: (a) preparingactive agent granules by (i) blending avanafil in particulate form witha first fraction of a disintegrant and a first fraction of a porousbinder, to form an initial mixture, and (ii) granulating the initialmixture for a predetermined time period at a predetermined temperature,to provide the active agent granules, wherein granulating is carried outin a solvent; (b) drying the active agent granules; (c) blending the dryactive agent granules with a lubricant, a second fraction of thedisintegrant, and a second fraction of a porous binder, to provide afinal formulation mixture; and (d) compacting the final formulationmixture to prepare the rapidly disintegrating oral dosage form.